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Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator-activated receptor gamma

ABSTRACT: The resolution of inflammation is an active process that is tightly regulated to achieve repair and tissue homeostasis. In the absence of resolution, chronic inflammation underlies the pathogenesis of chronic lung disease including Chronic Obstructive Pulmonary Disease (COPD) with recurrent exacerbations. Over the course of inflammation, macrophage programming transitions from inflammatory to pro-resolving, and is in part regulated by the nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ). In our previous work, we demonstrated an association between Fatty Acid Binding Protein 5 (FABP5) expression and PPARg activity in PBMCs. However, the role of FABP5 in macrophage programming is not yet defined, thus, we further investigated its interaction with PPARγ and its role in macrophage programming. Here, we demonstrate that FABP5 is necessary to initiate PPARγ activation and macrophage pro-resolving programming. We used the RNAscope tool in combination with co-immunofluorescence, immunoprecipitation, PPARγ activity assay, and chromatin immunoprecipitation to show that FABP5 and PPARγ not only interact but also regulate one another. By integrating flow cytometry, ELISA, assay for transposase-accessible chromatin by sequencing (ATAC-seq) and the Seahorse technology, we extend our findings to illustrate that lack of FABP5 expression promotes a glycolytic pro-inflammatory macrophage programming. Taken together, these data provide evidence that FABP5 and PPARγ reciprocally regulate each other’s expression and function, consistent with a positive feedback regulatory loop between the two to promote macrophage pro-resolving programming.

ORGANISM(S): Mus musculus

PROVIDER: GSE193748 | GEO | 2023/12/08

REPOSITORIES: GEO

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Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

Project description:Dunster2014 - WBC Interactions (Model1) This is a sub-model of a three-step inflammatory response modelling study. The model includes distinct populations of white blood cells namely, macrophages and active and apoptotic neutrophil populations. Neutrophil apoptosis rate is predicted to be crucial for the qualitative nature of the system. This model is described in the article: The resolution of inflammation: a mathematical model of neutrophil and macrophage interactions. Dunster JL, Byrne HM, King JR. Bull. Math. Biol. 2014 Aug; 76(8): 1953-1980 Abstract: There is growing interest in inflammation due to its involvement in many diverse medical conditions, including Alzheimer's disease, cancer, arthritis and asthma. The traditional view that resolution of inflammation is a passive process is now being superceded by an alternative hypothesis whereby its resolution is an active, anti-inflammatory process that can be manipulated therapeutically. This shift in mindset has stimulated a resurgence of interest in the biological mechanisms by which inflammation resolves. The anti-inflammatory processes central to the resolution of inflammation revolve around macrophages and are closely related to pro-inflammatory processes mediated by neutrophils and their ability to damage healthy tissue. We develop a spatially averaged model of inflammation centring on its resolution, accounting for populations of neutrophils and macrophages and incorporating both pro- and anti-inflammatory processes. Our ordinary differential equation model exhibits two outcomes that we relate to healthy and unhealthy states. We use bifurcation analysis to investigate how variation in the system parameters affects its outcome. We find that therapeutic manipulation of the rate of macrophage phagocytosis can aid in resolving inflammation but success is critically dependent on the rate of neutrophil apoptosis. Indeed our model predicts that an effective treatment protocol would take a dual approach, targeting macrophage phagocytosis alongside neutrophil apoptosis. This model is hosted on BioModels Database and identified by: BIOMD0000000616. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator-activated receptor gamma

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